This invention relates to the discovery that a group of 2-aryl-3-aroylbenzo[b]thiophenes are effective in modulating calcium channels, increasing the density of calcium channels in vascular and cardiac tissue, with no changes in inotropic or pressor response.
Replacement therapy with estrogen is generally acknowledged to produce beneficial effects on the cardiovascular system in postmenopausal women. See Knopt, Obstet. Gynecol., 72 23s-30s (1988). In postmenopausal women who receive estrogens, the cardiovascular mortality rate is reduced by about 30% to about 50%, and the cerebrovascular mortality rate is reduced by about 50%. See Stampfer et al., N. Engl. J. Med., 325, 756-762 (1991). Although these beneficial cardiovascular effects may involve alterations in lipid profile, recent data suggests that estrogen may also have beneficial effects on the vascular responses of atherosclerotic coronary arteries. See Gisclard et al., J. Pharmacol. and Experimental Therapeutics 244, 19-22 (1988); Williams et al., Circulation, 81, 1680-1687 (1990); Gangar et al., Lancet, 388, 839-842 (1991); and Williams et al., JACC, 20, 452-457 (1992). Both endothelial-independent and endothelial-dependent effects of estrogen have been described in vascular tissue. See Jiang et al., Br. J. Pharmacol., 104, 1033-1037 (1991 ); Jiang et. al., American Journal of Physiology, 32, H271-H275 (1992); Cheng and Gruetter, European Journal Of Pharmacol., 215, 171-176 (1992); Mugge et al., Cardiovas. Res., 27, 1939-1942 (1993); Salas et al., European Journal of Pharmacol., 258, 47-55 (1994); Williams et al., Circulation, 81, 1680-1687 (1990); Cheng et al., Life Sciences, 10, 187-191 (1994); Gilligan et al., Circulation, 89, 2545-2551 (1994); and Reis et al., Circulation, 89, 52-60 (1994). Several reports have also suggested that the vasodilating effects of estradiol and/or its ability to attenuate contractile responses may be mediated by inhibition of calcium influx via voltage dependent calcium channels. See Jiang et al., Br. J. Pharmacol., 104, 1033-1037 (1991); Jiang et. al., American Journal of Physiology, 32, H271-H275 (1992); Collins et al., Lancet, 341, 1264 (1993); Muck et al., Med. Sci. Res., 22, 19 (1994); and Salas et al., European Journal of Pharmacol., 258, 47-55 (1994). Others have postulated that estradiol may enhance cyclic AMP and cyclic GMP content, or increase ATP-sensitive potassium channels. See Mugge et al., Cardiovas. Res., 27, 1939-1942 (1993); Sudhir et al., Am. Heart J., 129, 726-732 (1995).
The 2-aryl-3-aroylbenzo[b]thiophene compounds that are used in the methods of this invention were first developed by Jones and Suarez as anti-fertility agents. See U.S. Pat. No. 4,133,814 (issued Jan. 9, 1979). These compounds are generally useful in suppressing the growth of mammary tumors. Jones later found that a group of these compounds are particularly useful for antiestrogen and antiandrogen therapy, especially in the treatment of mammary and prostatic tumors. See U.S. Pat. No. 4,418,068 (issued Nov. 29, 1983). One of these compounds, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene was clinically studied for the treatment of breast cancer. This compound is called raloxifene, formerly keoxifene.